The invention relates to novel 6-(substituted) methylenepenicillanic acids, and novel 6-(substituted)-hydroxymethylpenicillanic acids, certain esters and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, methods for their preparation and their use as beta-lactamase inhibitors and intermediates therefor.
One of the most well-known and widely used of the classes of antibacterial agents is the class known as the beta-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the beta-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain micro-organisms. It is thought that in many instances this resistance of a particular microorganism to a given beta-lactam antibiotic results because the microorganism produces a beta-lactamase. The latter substances are enzymes which cleave the beta-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when a beta-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a beta-lactamase inhibiting substance and a beta-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components.
Thus, according to the invention, there are provided new compounds which are 6-(substituted)methylenepenicillanic acids, their 1-oxides, 1,1-dioxides and esters thereof readily hydrolyzable in vivo. These new penicillanic acids and their esters readily hydrolyzable in vivo are potent inhibitors of microbial beta-lactamases. Accordingly, there is also provided a method for enhancing the effectiveness of beta-lactam antibiotics, using these novel acids, their salts and certain readily hydrolyzable esters thereof.
Still further, there are provided derivatives of 6-(substituted)methylenepenicillanic acids, their 1-oxides and 1,1-dioxides having a carboxy protecting group, said compounds being useful as chemical intermediates.
Yet further, there are provided 6-(substituted)-hydroxymethylpenicillanic acids, their 1-oxides, 1,1-dioxides and salts and esters thereof which are useful both as chemical intermediates and as beta-lactamase inhibitors.
European Patent Application No. 50,805 discloses compounds of the formula ##STR2## wherein n is zero, 1 or 2, R.sub.1 is CN or certain carbonyl moieties; R.sub.2 is hydrogen, lower alkyl or halogen and R.sub.3 is hydrogen or a readily hydrolyzable group, useful as beta-lactamase inhibitors. The same reference discloses 6-oxopenicillanic acid esters, the corresponding sulfoxides and sulfones as well as a method for their use in preparation of compounds of formula (III) by reaction with a phosphoran of formula R.sub.1 R.sub.2 C.dbd.P(C.sub.6 H.sub.5).sub.3.
United Kingdom Patent Application GB 2,053,220A discloses, inter alia, certain 6-methylene-1,1-dioxopenicillanic acids and esters of the above formula (III) where n is 2 and R.sub.1 and R.sub.2 independently denote hydrogen, an optionally substituted alkyl, aryl, optionally substituted cycloalkyl, an aralkyl or optionally substituted amino group, or together with the carbon atom to which they are attached, R.sub.1 and R.sub.2 form a 3 to 7-membered carbocyclic or heterocyclic ring.
U.S. Pat. No. 4,287,181 discloses certain 6-substituted penicillanic acid 1,1-dioxides and esters thereof wherein the 6-substituent is ##STR3## and, inter alia, R.sub.3 is H or alkanoyl and R.sub.4 is H, (C.sub.1 -C.sub.4)alkyl, phenyl, benzyl or pyridyl, which are useful as beta-lactamase inhibitors.